Research

Original Investigation | LESS IS MORE

Continuous Proton Pump Inhibitor Therapy and

the Associated Risk of Recurrent Clostridium difficile Infection
Emily G. McDonald, MD; Jonathon Milligan, MD; Charles Frenette, MD; Todd C. Lee, MD, MPH

Supplemental content at
IMPORTANCE Clostridium difficile infection (CDI) is associated with significant morbidity, jamainternalmedicine.com
mortality, and a high risk of recurrence. Proton pump inhibitor (PPI) use is associated with an CME Quiz at
initial episode of CDI, and PPIs are frequently overprescribed. For many, the use of PPIs could jamanetworkcme.com
likely be discontinued before CDI recurrence.

OBJECTIVES To determine whether PPI use was associated with a risk of initial CDI
recurrence, to assess what proportion of patients who developed CDI were taking a PPI for a
non–evidence-based indication, and to evaluate whether physicians discontinued
unnecessary PPIs in the context of CDI.

DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective cohort study of incident

health care–associated CDI cases to determine the association between continuous PPI use
and CDI recurrence within 90 days. The setting was 2 university-affiliated hospitals, the
417-bed Montreal General Hospital (Montreal, Quebec, Canada) and the 517-bed Royal
Victoria Hospital (Montreal, Quebec, Canada). The cohort consisted of 754 patients who
developed health care–associated CDI between January 1, 2010, and January 30, 2013, and
who survived for a minimum of 15 days after their initial episode of nosocomial CDI.

EXPOSURE Continuous PPI use.

MAIN OUTCOMES AND MEASURES Recurrence of CDI within 15 to 90 days of the initial
episode.

RESULTS Using a multivariable Cox proportional hazards model, the cause-specific hazard
ratios for recurrence were 1.5 (95% CI, 1.1-2.0) for age older than 75 years, 1.5 (95% CI, 1.1-2.0)
for continuous PPI use, 1.003 (95% CI, 1.002-1.004) per day for length of stay, and 1.3 (95%
CI, 0.9-1.7) for antibiotic reexposure. The use of PPIs was common (60.7%), with only 47.1%
of patients having an evidence-based indication. Proton pump inhibitors were discontinued
in only 3 patients with CDI.

Author Affiliations: Division of

CONCLUSIONS AND RELEVANCE After adjustment for other independent predictors of General Internal Medicine,
recurrence, patients with continuous PPI use remained at elevated risk of CDI recurrence. We Department of Medicine, McGill
suggest that the cessation of unnecessary PPI use should be considered at the time of CDI University Health Centre, Montreal,
Quebec, Canada (McDonald, Lee);
diagnosis.
McGill Centre for Quality
Improvement, Montreal, Quebec,
Canada (McDonald, Lee);
Department of Medicine, University
of Toronto, Toronto, Ontario, Canada
(Milligan); Division of Infectious
Diseases, Department of Medicine,
McGill University Health Centre,
Montreal, Quebec, Canada (Frenette,
Lee).
Corresponding Author: Emily G.
McDonald, MD, Division of General
Internal Medicine, Department of
Medicine, McGill University Health
Centre, 687 Pine Ave W, Room A421,
JAMA Intern Med. 2015;175(5):784-791. doi:10.1001/jamainternmed.2015.42 Montreal, QC H3A 1A1, Canada
Published online March 2, 2015. (emily.mcdonald@mail.mcgill.ca).

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 PPI Therapy and Recurrent C difficile Infection
C
lostridium difficile is the most common cause of infec-
tious diarrhea in hospitalized patients1 and is associ-
ated with significant attributable costs (US $11 000 per
nosocomial case2) and morbidity and risk of mortality.3 Even
when an initial episode of C difficile infection (CDI) is success-
fully treated, approximately 20% of patients will experience 1
or more recurrences.4 The management of patients with mul-
tiple recurrences is challenging, and therapeutic options are
limited. Therefore, when faced with a patient with an initial
episode of CDI, an important goal must be the prevention of
subsequent episodes.
A reasonable approach to preventing recurrence is to mini-
mize modifiable risk factors such as antibiotic exposure. Pro-
ton pump inhibitor (PPI) use is prevalent and has been iden-
tified as an important exposure before an initial episode of
CDI.3,5,6 Consequently, Health Canada7 and the US Food and
Drug Administration8 have released advisories that in all pa-
tient populations PPIs should be used at the lowest dosage pos-
sible for the shortest duration that is clinically indicated.
Despite associations with CDI and other recognized ad-
verse events,8-11 PPIs are still overprescribed.12-14 Given that
many patients receive these drugs without evidence-based in-
dications, we hypothesized that unnecessary PPI use could be
discontinued in patients with CDI to minimize recurrence risk.
This would be an intervention of negligible cost with substan-
tial potential benefit. Nevertheless, although the association
between PPI use and incident CDI is well established, the evi-
dence implicating PPIs with recurrence is limited to a few con-
flicting studies.15-18
The objectives of our study were 3-fold. First was to de-
termine whether PPI use was associated with a risk of initial
CDI recurrence. Second was to assess what proportion of pa-
tients who developed CDI were taking a PPI for a non–evidence-
based indication. Third was to evaluate whether physicians dis-
continued unnecessary PPIs in the context of CDI.
Methods
Ethics
Ethics approval was granted by the McGill University Health
Centre Research Ethics Board. Informed consent was waived.
Description of the Cohort
This was a retrospective cohort study consisting of all pa-
tients who developed an initial episode of health care–
associated CDI between January 1, 2010, and January 30, 2013,
and who survived for a minimum of 15 days after their initial
episode of nosocomial CDI. The study was conducted at 2 uni-
versity-affiliated hospitals, the 417-bed Montreal General Hos-
pital (Montreal, Quebec, Canada) and the 517-bed Royal Vic-
toria Hospital (Montreal, Quebec, Canada).
As per Quebec standards, health care–associated CDI cases
were those in which (1) symptoms occurred more than 3 days
after admission or (2) symptoms caused readmission in a pa-
tient who had been hospitalized within the previous 30 days
and who was not a resident in a long-term care facility. All po-
tential cases were adjudicated by an infection control nurse
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Original Investigation Research
for symptoms and were diagnosed by polymerase chain reac-
tion for toxin B. Patients who were polymerase chain reac-
tion positive without 3 episodes of diarrhea were excluded from
the study. Exceptions included patients with ileus, toxic mega-
colon, colitis determined by results from computed tomogra-
phy or colonoscopy, or autopsy-proven disease.
Patients within the cohort were evaluated for a recur-
rence of CDI, defined as recurrent symptoms (without alter-
native explanation) in association with a second positive
C difficile polymerase chain reaction assay occurring between
15 and 90 days after the initial episode. While the Society for
Healthcare Epidemiology of America and the Infectious Dis-
eases Society of America guidelines suggest that a recurrence
should be defined as occurring within 56 days of the initial
episode,19 they recognize that the definition is not evidence
based. We chose to include episodes occurring between days
57 and 90 because we believed that they were also clinically
important, as well as to ensure that our results would be
directly comparable to those of the conflicting large observa-
tional studies15,16 that have previously addressed this issue.
Censoring occurred at CDI recurrence or at death within 90
days. Those who did not die or experience a recurrence were
censored at 90 days.
There were 809 patients identified, of whom 55 were ex-
cluded because they died before day 15 and therefore could
never have had a recurrence. This left a cohort of 754 patients
whose cases were analyzed.
Exposure Assessment
The main exposure of interest was continuous PPI use. Expo-
sure was defined as the receipt of a PPI at the time of the ini-
tial episode of C difficile with either (1) ongoing exposure for
at least 75% of days in the hospital in those who remained hos-
pitalized or (2) a discharge prescription for a PPI that was valid
beyond 90 days after the initial episode. To ensure that pa-
tients with CDI recurrence remained exposed, they were also
reevaluated at the time of recurrence for a valid PPI prescrip-
tion from at least 48 hours before recurrence. More than 90%
of exposed patients were receiving pantoprazole sodium (40
mg daily) because this is one of only 2 PPIs (along with dis-
solvable lansoprazole) on our hospital formularies.
Other Demographics
We extracted information on the treatment of the initial epi-
sode of CDI, the unit that the infection was attributed to (medi-
cal, surgical, critical care, or other), the admitting hospital (to
control for differences in local colonization pressure), and
length of stay. In our hospitals, the duration of initial treat-
ment of CDI is 14 days.
Age, sex, and date of death (if deceased) were obtained
from the patient registration database. Patient comorbidities
were obtained from International Statistical Classification of
Diseases, 10th Revision, data manually abstracted by medical
record personnel during the index admission (eAppendix in
the Supplement). Vancomycin-resistant enterococci and
methicillin-resistant Staphylococcus aureus colonization sta-
tus were obtained from the hospitals’ respective microbiol-
ogy laboratories.
(Reprinted) JAMA Internal Medicine May 2015 Volume 175, Number 5 785
 Research Original Investigation PPI Therapy and Recurrent C difficile Infection

Table 1. Analysis of Risk Factors for Clostridium difficile Death or Recurrence Within 90 Days for 754 Patients in the Cohort

No. (% of Total No.) Value (95% CI)

Deaths
Without
Patient Recurrence Recurrences Survivors
Characteristic (n = 52) (n = 193) (n = 509) Death CSHR Recurrence CSHR Recurrence sHR
Age >75 y 34 (65.4) 98 (50.8) 184 (36.1) 2.8 (1.6-5.0)a 1.6 (1.2-2.1)a 1.5 (1.1-2.0)b
Male sex 27 (51.9) 104 (53.9) 264 (51.9) 1.0 (0.6-1.8) 1.1 (0.8-1.4) 1.1 (0.8-1.4)
Continuous PPI use 40 (76.9) 132 (68.4) 286 (56.2) 2.2 (1.2-4.3)c 1.4 (1.1-2.0)c 1.4 (1.0-1.9)c
Hypertension 31 (59.6) 118 (61.1) 261 (51.3) 1.3 (0.8-2.3) 1.4 (1.1-1.9)c 1.4 (1.0-1.9)c
a c
Coronary artery 27 (51.9) 69 (35.8) 131 (25.7) 2.6 (1.5-4.6) 1.4 (1.1-1.9) 1.3 (1.0-1.8)c
disease
Congestive heart 16 (30.8) 43 (22.3) 65 (12.8) 2.7 (1.5-4.9)a 1.6 (1.2-2.3)b 1.5 (1.1-2.1)c
failure
Atrial fibrillation 12 (23.1) 43 (22.3) 84 (16.5) 1.4 (0.7-2.7) 1.3 (0.9-1.9) 1.3 (0.9-1.8)
Diabetes mellitus 19 (36.5) 49 (25.4) 122 (24.0) 1.7 (0.9-3.0) 1.1 (0.8-1.5) 1.0 (0.8-1.4)
Renal disease 30 (57.7) 66 (34.2) 130 (25.5) 3.4 (1.9-5.9)a 1.3 (0.9-1.7) 1.2 (0.9-1.6)
Lung disease 8 (15.4) 46 (23.8) 101 (19.8) 0.6 (0.3-1.4) 1.3 (0.9-1.8) 1.3 (0.9-1.8)
Previous stroke 4 (7.7) 10 (5.2) 23 (4.5) 1.7 (0.6-4.8) 1.0 (0.5-2.0) 1.0 (0.5-1.9)
Hematologic cancer 11 (21.2) 21 (10.9) 43 (8.4) 2.7 (1.4-5.2)b 1.2 (0.7-1.8) 1.1 (0.7-1.7)
Solid cancer 15 (28.8) 49 (25.4) 105 (20.6) 1.5 (0.8-2.7) 1.3 (0.9-1.7) 1.2 (0.9-1.7)
c c
Thromboembolism 11 (21.2) 32 (16.6) 49 (9.6) 2.2 (1.1-4.2) 1.5 (1.1-2.3) 1.5 (1.0-2.2)c
Cirrhosis 1 (1.9) 10 (5.2) 16 (3.1) 0.6 (0.1-4.2) 1.7 (0.9-3.1) 1.7 (0.9-3.2)
Peptic ulcer disease 4 (7.7) 8 (4.1) 17 (3.3) 2.1 (0.8-5.9) 1.1 (0.5-2.2) 1.1 (0.5-2.2)
Length of stay >10 d 52 (100) 157 (81.3) 387 (76.0) NA 1.2 (0.9-1.8) 1.2 (0.8-1.6)
Vancomycin-resistant 16 (30.8) 32 (16.6) 58 (11.4) 2.9 (1.6-5.3)a 1.3 (0.9-1.9) 1.2 (0.8-1.7)
enterococci
colonization
Methicillin-resistant 7 (13.5) 22 (11.4) 30 (5.9) 1.8 (0.8-4.2) 1.7 (1.1-2.7)c 1.7 (1.1-2.6)c
Staphylococcus aureus
colonization
Unit where acquired
Montreal General 28 (53.8) 122 (63.2) 250 (49.1) 1.1 (0.6-1.8) 1.6 (1.2-2.2)b 1.6 (1.2-2.2)a
Hospital site
Medical unit 23 (44.2) 63 (32.6) 124 (24.4) 2.3 (1.3-3.9)b 1.4 (1.0-1.9)c 1.3 (1.0-1.8)
Inpatient therapy
Undocumented, 6 (11.5) 41 (21.2) 95 (18.7) 0.6 (0.3-1.4) 1.2 (0.8-1.7) 1.3 (0.9-1.8)
all outpatient
Documented 46 (88.5) 152 (78.8) 414 (81.3) NA NA NA
(n = 612)
Metronidazole 14/46 (30.4) 77/152 (50.7) 209/414 (50.5) 0.4 (0.2-0.8)c NA NA
monotherapy
Day 15 NA NA NA NA 2.3 (1.4-4) 2.3 (1.4-4)
Day 28 NA NA NA NA 1.5 (0.7-3.4) 1.6 (0.7-3.4)
Day 56 NA NA NA NA 0.7 (0.2-2.4) 0.7 (0.2-2.5)
Any receipt of 32/46 (69.6) 75/152 (49.3) 205/414 (49.5) 2.3 (1.2-4.4)c NA NA
vancomycin
Day 15 NA NA NA NA 0.4 (0.2-0.7) 0.4 (0.3-0.7)
Day 28 NA NA NA NA 0.6 (0.3-1.4) 0.6 (0.3-1.4)
Day 56 NA NA NA NA 1.5 (0.4-5.2) 1.4 (0.4-4.9)
Vancomycin 9 (17.3) 24 (12.4) 64 (12.6) NA 1.0 (0.6-1.5) 0.9 (0.6-1.5)
monotherapy
Day 15 NA NA NA 0.4 (0.1-1.6) NA NA
Day 28 NA NA NA 0.7 (0.1-4.7) NA NA
Day 56 NA NA NA 2.3 (0.1-40.5) NA NA
Combination 9 (17.3) 23 (11.9) 56 (11.0) 1.5 (0.7-3.1) 1.1 (0.7-1.7) 1.1 (0.7-1.7)
therapy

(continued)

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 PPI Therapy and Recurrent C difficile Infection Original Investigation Research

Table 1. Analysis of Risk Factors for Clostridium difficile Death or Recurrence Within 90 Days for 754 Patients in the Cohort (continued)

No. (% of Total No.) Value (95% CI)

Deaths
Without
Patient Recurrence Recurrences Survivors
Characteristic (n = 52) (n = 193) (n = 509) Death CSHR Recurrence CSHR Recurrence sHR
Sequential therapy 14 (26.9) 28 (14.5) 85 (16.7) 1.7 (0.9-3.2) NA NA
Day 15 NA NA NA NA 0.5 (0.2-1) 0.5 (0.2-0.9)
Day 28 NA NA NA NA 0.6 (0.2-1.7) 0.6 (0.2-1.5)
Day 56 NA NA NA NA 1.1 (0.2-5.1) 1 (0.3-4.3)
High-dose 20/46 (43.5) 55/152 (36.2) 147/414 (35.5) 1.4 (0.8-2.5) NA NA
vancomycin, if anyd
Day 15 NA NA NA NA 0.5 (0.3-1.0) 0.5 (0.3-0.9)
Day 28 NA NA NA NA 0.7 (0.3-1.6) 0.7 (0.3-1.6)
Day 56 NA NA NA NA 1.4 (0.4-4.9) 1.3 (0.4-4.5)
Antibiotic reexposure 35/48 (72.9) 78/170 (45.9) 144/438 (32.9) 4.9 (2.5-9.4)a 1.5 (1.1-2.0)b 1.4 (1.0-1.9)c
(n = 656)
Reexposure data 4 (7.7) 23 (11.9) 71 (13.9) 0.5 (0.2-1.5) 0.9 (0.6-1.4) 0.9 (0.6-1.4)
missing (n = 98)
c
Abbreviations: CSHR, cause-specific hazard ratio; NA, not applicable; PPI, P < .05.
proton pump inhibitor; sHR, subdistribution hazard ratio. d
High-dose vancomycin refers to dosages of at least 250 mg by mouth 4 times
a
P < .001. daily.
b
P < .01.

Antibiotic Reexposure
Ninety-nine percent (752 of 754) of patients were exposed to an-
tibiotics before the initial episode of C difficile. We obtained in-
hospital antibiotic reexposure data from our hospital phar-
macy database following the standard 14 days of therapy for
index CDI (within 15-90 days of the initial episode).
Process of Evaluating Indications for PPIs Use
A general internist (E.G.M.) reviewed the indications for PPI
use through a medical record review of all consecutive pa-
tients admitted to a medical clinical teaching unit or to a criti-
cal care unit (191 of 493 PPI users [38.7%]). One hundred of these
medical records were subsequently reviewed by a second phy-
sician (J.M.) for an independent verification of the indica-
tion. κ Agreement was 0.94. Consensus for 3 cases of disagree-
ment was reached after discussion with a third physician
(T.C.L.). Patients admitted to these units (and not to surgical
units) were chosen because they have detailed admission notes,
providing the most accurate history obtainable to determine
the rationale for PPI therapy (eAppendix in the Supplement).
tant potential confounder included in all models. All variables
in the final model were checked for significant interactions.
The proportional hazards assumption was tested by in-
cluding a factor × time interaction for all variables. If this led
to violation of the proportional hazards assumption, the in-
teraction with time was included in the model as the means
of correction of that violation, and the results for such vari-
ables are presented for days 15, 28, and 56.
Data were missing for both initial antibiotic therapy and
antibiotic reexposure. For our multivariable analysis, we im-
puted these variables with multiple imputation using chained
equations.23 Imputation models included the variables to be
included in the analysis models. Twenty imputations were per-
formed using logit for binary variables. Convergence was veri-
fied graphically, and the residuals were plotted against the fit-
ted values to evaluate model fit. A complete case analysis was
also performed to confirm that the conclusions were not
changed by the imputation technique.

Statistical Analysis
With statistical software (STATA, version 13; StataCorp LP), we
used a Cox proportional hazards model to determine the cause-
specific hazards ratios for both initial recurrence and death as
a competing risk. 20,21 We also performed competing risk
regression22 to determine subdistribution hazard ratios for both
end points, and we present both analyses for comparison.21
We first conducted a univariate analysis looking for associa-
tions between comorbid conditions and C difficile recurrence.
Factors that were associated with P < .25 and those believed a
priori to be important were considered for inclusion in the mul-
tivariable models. Backward elimination was then used to arrive
at the final models, with antibiotic reexposure being an impor-
Results
Among 754 eligible patients, there were 52 deaths without re-
currence (6.9%), 193 documented recurrences (25.6%), and 509
survivors without documented recurrence within 90 days
(67.5%). The comorbidities and clinical characteristics of these
patients are listed in Table 1. Among 193 patients who experi-
enced a recurrence, 157 recurrences (81.3%) occurred be-
tween days 15 and 56. The distribution of the timing of all 193
recurrences was as follows: 15 to 21 days (37 patients [19.2%]),
22 to 28 days (43 patients [22.3%]), 29 to 35 days (28 patients
[14.5%]), 36 to 42 days (24 patients [12.4%]), 43 to 49 days (12
patients [6.2%]), 50 to 56 days (13 patients [6.7%]), and 57 to
90 days (36 patients [18.7%]).

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 Research Original Investigation PPI Therapy and Recurrent C difficile Infection

mycin treatment of the initial episode. The cause-specific haz-

Table 2. Differences Between Users and Nonusers of PPIsa
ards ratios and subdistribution hazard ratios are listed in
PPI Users PPI Nonusers Table 3.
Variable (n = 458) (n = 296)
Age, median (IQR), y 71.5 (60-80) 69.5 (56-82) Among 458 of 754 patients (60.7%) who were taking a
Male sex 230 (50.2) 165 (55.7)
PPI at CDI diagnosis, 191 (41.7%) underwent medical record
review, of whom 30 of 191 (15.7%) were cases and 161 of 191
Diabetes mellitusb 133 (29.0) 57 (19.3)
(84.3%) were controls. Ninety of these 191 PPI users (47.1%)
Renal disease 145 (31.7) 81 (27.4)
had an evidence-based indication for therapy (Table 4). The
Hypertensionc 265 (57.9) 145 (49.0)
most common evidence-based indication for PPI use was age
Coronary artery diseasec 152 (33.2) 75 (25.3)
older than 60 years with 2 other concurrent risk factors for
Lung disease 102 (22.3) 53 (17.9)
peptic ulcer disease (39 patients [20.4%]). Proton pump
Previous stroke 25 (5.5) 12 (4.1)
inhibitor use was discontinued in only 3 of 458 patients
Congestive heart failured 95 (20.7) 29 (9.8)
(0.6%).
Atrial fibrillation 93 (20.3) 46 (15.5)
Thromboembolismb 70 (15.3) 22 (7.4)
Hematologic cancer 41 (9.0) 34 (11.5)
Solid cancer 102 (22.3) 67 (22.6) Discussion
Peptic ulcer diseaseb 25 (5.5) 4 (1.4) In this retrospective cohort study, 754 patients with an ini-
Cirrhosis 21 (4.6) 6 (2.0) tial episode of health care–associated CDI were evaluated to
Methicillin-resistant Staphylococcus 41 (9.0) 18 (6.1) determine if PPI use was associated with CDI recurrence.
aureus colonization
Recurrence was common, occurring in 193 of 754 patients
Vancomycin-resistant enterococci 75 (16.4) 31 (10.5)
colonizationc (25.6%) within 90 days. After adjustment using 2 different
Length of stay >10 dd 382 (83.4) 214 (72.3) but complementary methods of accounting for the compet-
Outcomes ing risk of death, patients who were continuous users of
Death within 90 db 47 (10.3) 14 (4.7) PPIs had a cause-specific hazard ratio of 1.5 (95% CI, 1.1-2.0)
Recurrence within 90 db 132 (28.8) 61 (20.6) and a subdistribution hazard ratio of 1.4 (95% CI, 1.1-1.9) for
Unit where acquired CDI recurrence. Probable overuse of PPIs was seen in more
Montreal General Hospital site 230 (50.2) 170 (57.4)
than 50%. Despite this, PPI use was were almost never dis-
continued.
Medical unit 132 (28.8) 78 (26.4)
Although the association between PPI use and incident CDI
Surgical unit 223 (48.7) 147 (49.7)
is well established, few studies have looked at the association
Other unit 56 (12.2) 37 (12.5)
of PPI use with recurrent disease. Recurrences are associated
ICU/CCU 47 (10.3) 34 (11.5)
with a higher attributable cost, increased length of stay, and
Inpatient therapy (n = 612) (n = 436) (n = 176)
greater morbidity and mortality than an initial episode of CDI.31
Metronidazole monotherapy 203 (46.6) 97 (55.1)
Recurrent CDI is difficult to treat, with patients who experi-
Vancomycin monotherapy 75 (17.2) 22 (12.5)
ence an initial episode of recurrence having a 40% chance of
Combination therapy 59 (13.5) 29 (16.5)
developing a second recurrence and a 60% chance of further
Sequential therapyc 99 (22.7) 28 (15.9) recurrences.32,33
Any receipt of vancomycin 233 (53.4) 79 (44.9) A PubMed search identified 4 prior studies15-18 examin-
High-dose vancomycin, if anye 163/233 (70.0) 59/79 (74.7) ing the association between PPI use and recurrent CDI. Two
Antibiotic reexposure (n = 656) 170/412 (41.3) 87/244 (35.7) of these studies 1 7,1 8 involved fewer than 150 patients
Abbreviations: ICU/CCU, intensive care unit/coronary care unit; each and demonstrated an association between PPI use and
IQR, interquartile range; PPI, proton pump inhibitor. recurrence.
a
All data are given as the number (percentage) unless otherwise indicated. The association was strengthened with the findings by
b
P < .01. Linsky et al16 in a mixed population of 1166 inpatients and
c
P < .05. outpatients diagnosed as having CDI by enzyme-linked
d
P < .001. immunoabsorbent assay. In their cohort, 45% of patients
e
High-dose vancomycin refers to dosages of at least 250 mg by mouth 4 times were taking a PPI. After adjusting for comorbidities, antibi-
daily. otic reexposure, and censoring for death, they established
that PPI use was associated with CDI recurrence (hazard
The PPI users differed from nonusers in multiple ways ratio, 1.4; 95% CI, 1.1-1.8).
(Table 2). Most important, they were more likely to experi- In contrast, Freedberg et al15 analyzed hospitalized pa-
ence a CDI recurrence (28.8% vs 20.6%, P = .007) or to die tients with CDI and found no association among 894 patients
(10.3% vs 4.7%, P = .007) within 15 to 90 days of the initial with incident CDI diagnosed by polymerase chain reaction. Ex-
episode. posure was defined as PPI receipt for a minimum of 2 days dur-
In the multivariable analysis, the following remained in- ing CDI therapy (62% were exposed). This definition differs
dependently associated with the rate of recurrence: age older from other studies that have looked at continuous exposure.
than 75 years, continuous PPI use, length of stay, and vanco- Unlike in the study by Linsky et al16 and in the present study,

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 PPI Therapy and Recurrent C difficile Infection Original Investigation Research

Table 3. Unadjusted and Adjusted CSHRs for Initial Relapse of Clostridium difficile and Estimated sHRs
for Recurrence Using Competing Risk Regression

Value (95% CI)

Crude Adjusted Crude Adjusted
Predictor Relapse CSHR Relapse CSHR Relapse sHR Relapse sHR
Age >75 y 1.6 (1.2-2.1) 1.5 (1.1-2.0) 1.5 (1.1-2.0) 1.4 (1.1-1.9)
Continuous PPI use 1.4 (1.1-2.0) 1.5 (1.1-2.0) 1.4 (1.0-1.9) 1.4 (1.1-1.9)
a
Antibiotic reexposure 1.4 (1.0-1.9) 1.3 (0.9-1.7) 1.3 (1-1.8) 1.2 (0.9-1.6)
Length of stay, per day 1.003 1.003 1.003 1.003
(1.002-1.005) (1.002-1.004) (1.002-1.005) (1.002-1.004)
Vancomycin treatment
of the episodea Abbreviations: CSHR, cause-specific
Day 15 0.4 (0.2-0.8) 0.4 (0.2-0.7) 0.4 (0.2-0.7) 0.4 (0.2-0.7) hazard ratio; PPI, proton pump
Day 28 0.5 (0.2-1.3) 0.5 (0.2-1.3) 0.5 (0.2-1.3) 0.5 (0.2-1.3) inhibitor; sHR, subdistribution hazard
ratio.
Day 56 1.1 (0.3-4.1) 1.0 (0.3-3.9) 1.0 (0.3-3.8) 1.0 (0.3-3.8) a
Includes imputed values.

Freedberg et al15 did not adjust for antibiotic reexposure, po-

Table 4. Indications for PPI Use Among 191 Patients Who Underwent
tentially confounding the analysis. Medical Record Review
No. (%)
Strengths and Limitations of the Study Indication for PPI Use24-30 (n = 191)
Our observational study has the potential for unmeasured and No indication 101 (52.9)
residual confounding. Except for peak white blood cell count Age >60 y with 2 other risk factorsa 39 (20.4)
and the number of episodes of diarrhea, we believe that we ad-
Presumed upper gastrointestinal bleeding 17 (8.9)
justed for many of the confounders associated with recurrent
Symptomatic nonulcer dyspepsia reflux disease 15 (7.9)
CDI.34 Although we do not routinely type for C difficile strain, within 3 mob
provincially this has not changed over the study period, and Erosive esophagitis 9 (4.7)
roughly 50% are North American pulsed-field gel electropho- Endoscopically proven peptic ulcer disease 8 (4.2)
resis type 1 (NAP1) in Quebec.
Dual antiplatelet therapy, age <60 y 1 (0.5)
There is a possibility that patients who experienced CDI
Antiplatelet and anticoagulant therapy, age <60 y 1 (0.5)
recurrence at another center would not have been captured in
Eosinophilic esophagitis 0
our study. However, patients in our jurisdiction are routinely
routed back to their usual hospital, and we believe that we cap- Helicobacter pylori eradication 0

tured most recurrences. Abbreviation: PPI, proton pump inhibitor.

Rehospitalization and outpatient visits may be important
risk factors for the receipt of a PPI and for recurrent CDI. While
we were unable to specifically adjust for these interactions, we
have attempted to minimize this confounding through the ad-
justment for age, comorbid illnesses, admission to a medical
unit, and length of stay.
Although we did not have a strict method to determine
PPI adherence in the community, we attempted to minimize
incorrectly labeling patients with recurrence as being
exposed by reverifying ongoing PPI use at the time of CDI
recurrence. While this may have introduced differential mis-
classification bias in the patients who did not experience a
recurrence, we believe that this would only have served to
bias our study toward the null and therefore does not invali-
date our conclusions.
Finally, patients whose initial CDI therapy was extended
beyond 14 days were not examined separately. This repre-
sented less than 5% of patients, and we believe that this is un-
likely to have nullified the association we observed between
PPI use and recurrent CDI.
The strengths of our study are the large number of par-
ticipants, our use of both the Cox proportional hazards model
and competing risk regression model for dealing with the com-
peting risk of death, the adjustment for potential confound-
a
Prescription for a nonsteroidal anti-inflammatory drug, antiplatelet,
anticoagulant, or systemic corticosteroid or history of a high-risk
gastrointestinal bleed.
b
Refractory to a trial of histamine blockers or a nonpharmacological
intervention.
ers (including antibiotic reexposure), and a reasonable defi-
nition of continuous PPI exposure. To date, this is also the
largest study to enumerate whether PPIs prescribed in the
population with CDI are for evidence-based indications, as well
as to demonstrate that their use is almost never discontinued
in the context of infection.
Options for the Prevention of Recurrent CDI
Currently available options for the prevention of recurrent
CDI are expensive, are difficult to access, and have limited
evidence. Fidaxomicin is potentially equivalent to oral
vancomyc in for the initial treatment of disease and
decreased the rates of recurrence (15.4% vs 25.3%, P = .005)
when evaluated at days 36 to 40 for non-NAP1 strains. 35
In our hospitals, fidaxomicin is not widely accessible
b e c a u s e t h e Q u e b e c f o r m u l a r y c it e s l i m it e d c o s t-
effectiveness vs that of vancomycin. Another emerging
viable treatment option, fecal transplantation,36 is also not

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 Research Original Investigation PPI Therapy and Recurrent C difficile Infection

widely available and is subject to governmental restrictions
in many countries.
By contrast, PPI use is common, it is associated with CDI re-
currence in 2 large observational studies,15,16 and the associa-
tion is biologically plausible given the effect of PPI therapy on
the gut microbiome.37 For more than half of the patients with
incident CDI, we have shown that the indication for PPI use is
not evidence based and have demonstrated that their PPI could
be safely discontinued. The cost of PPI discontinuation is neg-
ligible, and tapering the PPI dosage before discontinuation may
help to curb any complications such as symptoms of rebound
hyperacidity. In the absence of a randomized clinical trial clearly
demonstrating that ongoing nonindicated PPI use is safe, we sug-
gest that the use of non–evidence-based PPIs should almost cer-
tainly be discontinued in the context of CDI.
Conclusions
New drugs and fecal transplantation may represent future treat-
ments of CDI. In today’s era of choosing wisely, we propose that
the prevention of CDI recurrence should begin with the ces-
sation of unnecessary PPIs, a potentially unnecessary and fre-
quently overused class of medications.

ARTICLE INFORMATION /recall-alert-rappel-avis/hc-sc/2012/13651a-eng with outcomes in Clostridium difficile colitis. Am J

Accepted for Publication: January 7, 2015. .php. Accessed January 20, 2015. Health Syst Pharm. 2007;64(22):2359-2363.

Published Online: March 2, 2015.
doi:10.1001/jamainternmed.2015.42.
Author Contributions: Drs McDonald and Lee had
full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: McDonald, Frenette,
Lee.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: McDonald, Frenette, Lee.
Statistical analysis: McDonald, Lee.
Administrative, technical, or material support:
Milligan.
Study supervision: Frenette, Lee.
Conflict of Interest Disclosures: None
reported.
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